title: Clinical optimization of antigen specific modulation of type 1 diabetes with the plasmid DNA platform.
abstract: Some clinical trials in humans have aimed at modulation of type 1 diabetes (T1D) via alteration of the immune response to putative islet cell antigens, particularly proinsulin and insulin, glutamic acid decarboxylase and the peptide, DiaPep 277, derived from heat shock protein 60. The focus here is on development of a specially engineered DNA plasmid encoding proinsulin to treat T1D. The plasmid is engineered to turn off adaptive immunity to proinsulin. This approach yielded exciting results in a randomized placebo controlled trial in 80 adult patients with T1D. The implications of this trial are explored in regards to the potential for sparing inflammation in islets and thus allowing the functioning beta cells to recover and produce more insulin. Strategies to further strengthen the effects seen thus far with the tolerizing DNA plasmid to proinsulin will be elucidated. The DNA platform affords an opportunity for easy modifications. In addition standard exploration of dose levels, route of administration and frequency of dose are practical. Optimization of the effects seen to date on C-peptide and on depletion of proinsulin specific CD8 T cells are feasible, with expected concomitant improvement in other parameters like hemoglobin A1c and reduction in insulin usage. T1D is one of the few autoimmune conditions where antigen specific therapy can be achieved, provided the approach is tested intelligently. Tolerizing DNA vaccines to proinsulin and other islet cell autoantigens is a worthy pursuit to potentially treat, prevent and to perhaps even 'cure' or 'prevent' type 1 diabetes.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045-6511, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Gottlieb
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
mesh_terms: D056704:Adaptive Immunity; D001324:Autoantigens / Q000276:immunology; D002096:C-Peptide / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D010957:Plasmids; D011384:Proinsulin / Q000276:immunology* / Q000378:metabolism; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D001324:Autoantigens; D002096:C-Peptide; D006442:Glycated Hemoglobin; D011384:Proinsulin; D019444:Vaccines, DNA; C517652:hemoglobin A1c protein, human
keywords: CD8 T cell;; Proinsulin; Tolerance;; Type 1 diabetes;